P1109: TRIAL IN PROGRESS: PHASE 1B/2 TRIAL OF TAZEMETOSTAT IN COMBINATION WITH VARIOUS TREATMENTS IN PATIENTS WITH RELAPSED OR REFRACTORY HEMATOLOGIC MALIGNANCIES
Authors: A. Bessudo, D. Greenwald, M. H. Kazemi, A. Mahindra, L. Shunyakov, M. Sondhi, H. O’Connor, Y. Chen, J. Yang, G. Salles
Journal: HemaSphere (2022)

Background: Enhancer of zeste homolog 2 (EZH2), an epigenetic regulator, suppresses key cellular checkpoints and differentiation pathways to maintain the oncogenic characteristics of germinal center B cells. In addition to activity in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), EZH2 inhibitors induced cell cycle arrest and apoptosis in preclinical studies of multiple myeloma (MM). Tazemetostat (TAZ), an oral selective EZH2 inhibitor, is approved for treatment of relapsed or refractory (R/R) follicular lymphoma. Preclinical studies demonstrated antiproliferative and synergistic effects of TAZ + lenalidomide (LEN), a Bruton tyrosine kinase inhibitor (BTKi), and daratumumab, pomalidomide, and dexamethasone (mAbPD) in DBLCL, MCL, and MM cell lines, respectively. LEN is effective for DLBCL and is approved in combination with tafasitamab-cxix, a CD19-directed cytolytic antibody (CD19 antibody [Ab]), for R/R DLBCL. Acalabrutinib, a BTKi, is approved in MCL, and mAbPD showed clinical activity in R/R MM. Aims: The aim of this study is to examine the efficacy and safety of TAZ + CD19 Ab, LEN, BTKi, or mAbPD in patients (pts) with R/R hematologic malignancies. Methods: This trial is a 2-part, multicenter, open-label, safety, efficacy, signal-finding, multi-arm phase 1b/2 study of TAZ plus various treatment regimens for hematologic malignancies (NCT05205252). Phase 1b is a dose escalation safety run-in; phase 2 is a dose expansion study. Currently, there are 4 treatment arms (Table). Written informed consent will be obtained upon enrollment. Eligible pts are adults (aged ≥18 y) with an ECOG performance status 0–1 (phase 1b) or 0–2 (phase 2) and measurable disease by Lugano classification for arms 1–3 or IMWG 2016 criteria for arm 4. Pts with severe concurrent disease are excluded from this study. During the phase 1b safety run-in portion of the study, pts will be enrolled in 3 dose escalation cohorts of TAZ 400 mg, 600 mg, and 800 mg. Pts in all novel treatment combinations (arms 1, 3, 4) will start at the lowest TAZ dose of 400 mg, and treatment combinations previously studied (arm 2) will start at TAZ 800 mg. All pts will receive TAZ orally twice daily in continuous cycles. All combination partners will be administered per their respective package insert or investigator brochure. The phase 1b portion endpoint summarizes treatment-emergent dose-limiting toxicities and adverse events to inform the recommended phase 2 dose for each arm. The primary endpoint for all arms in phase 2 is objective response rate; key secondary endpoints include progression-free survival, duration of response, overall survival, and safety. Results: As of February 9, 2022, no pts are enrolled at 1 active site; additional sites are in startup. Image:Summary/Conclusion: This phase 1b/2 study will provide insights into the efficacy and safety of TAZ + CD19 Ab, LEN, BTKi, or mAbPD in pts with R/R hematologic malignancies.